Thrombopoietin is a cytokine consisting of 332 amino acids that increases platelet production by stimulating differentiation and proliferation of hematopoietic stem cells, megakaryocytic progenitor cells and megakaryocytes mediated by its receptor and therefore is promising as a drug for hematological disorders. Recent reports that it stimulates differentiation and proliferation of vascular endothelial cells and endothelial progenitor cells have raised expectations of therapeutic angiogenesis, anti-arteriosclerosis and prevention of cardiovascular events (Microvasc. Res., 1999:58, 108-113, Circ. Res., 1999:84, 785-796, Blood 2001:98, 71a). Biologically active substances which have been known so far to regulate platelet production through the thrombopoietin receptor include, in addition to thrombopoietin itself, the low molecular weight peptides having affinity for the thrombopoietin receptor disclosed in JP-A-10-72492 (WO96/40750), WO96/40189, WO98/25965 and the like. As a result of search for nonpeptidic low molecular weight compounds that increase platelet production mediated by the thrombopoietin receptor, several reports have been made on low molecular weight compounds having affinity for the thrombopoietin receptor.    1) Applications filed by Hokuriku Seiyaku Co., Ltd. relating to 1,4-benzodiazepine derivatives (JP-A-11-1477 and JP-A-11-152276)    2) International Laid-open Patent Applications filed by Shionogi & Co., Ltd. (WO01/07423, WO01/53267, WO02/059099 and WO02/059100)    3) International Laid-open Patent Applications filed by SmithKline Beecham Corp (WO00/35446, WO00/66112, WO01/34585, WO01/17349, WO01/39773, WO01/21180, WO01/89457, WO02/49413 and WO02/085343)    4) Japanese Laid-open Patent Application filed by Torii Pharmaceutical Co., Ltd. (JP-A-2001-97948)    5) International Laid-open Patent Application filed by Roche Diagnostics GMBH (WO99/11262)    6) International Laid-open Patent Application filed by Yamanouchi Pharmaceutical Co., Ltd. (WO02/06275)
Meanwhile, xanthocillin analogues are not only known to have broad antibacterial spectra but also reported to have antiviral action, aromatase inhibitory action (JP-A-07-69883), antitumor medicine (JP-A-02-304058 and JP-A-04-182427), anthelmintic agent (JP-A-02-40324), prostaglandin synthesis inhibitory action and platelet aggregation inhibitory action. However, nothing has been reported on affinity for or agonistic action on the thrombopoietin receptor.
Thrombopoietin and low molecular weight peptides having affinity for the thrombopoietin receptor are likely to be easily degraded in the gastrointestinal tract and are usually difficult to orally administer. As to thrombopoietin itself, the appearance of anti-thrombopoietin antibodies have been reported.
Besides, though it is probably possible to orally administer nonpeptidic low molecular weight compounds, no practical drugs have been put on the market.
Therefore, orally administrable low molecular weight compounds having excellent affinity for and agonistic action on the thrombopoietin receptor as preventive, therapeutic and improving agents for diseases against which activation of the thrombopoietin receptor is effective have been demanded. Specifically, low molecular weight compounds which can serve as platelet increasing agents or increasing agents for other blood cells by stimulating differentiation and proliferation of hematopoietic stem cells, megakaryocytic progenitor cells and megakaryocytes or low molecular weight compounds which can be used for therapeutic angiogenesis or as preventive and therapeutic agents for arteriosclerosis by stimulating endothelial cells and endothelial progenitor cells have been demanded.